My overall goal is to become an independent scientist in the obesity and diabetes field. As an Instructor in the Endocrine Division at Beth Israel Deaconess Medical Center in Boston my research has focused on the role of protein tyrosine phosphatases (PTPs) in the pathogenesis of insulin resistance. Obesity, an insulin-resistant state, is a major risk factor for type 2 diabetes. Increased expression and activity of protein tyrosine phosphatase 1B (PTP1B) are observed in muscle and adipose tissue of obese, insulin-resistant animals and humans, and have been implicated in causing insulin resistance. Transgenic PTP1B overexpression in skeletal muscle of mice is sufficient to impair muscle insulin action and cause whole body insulin resistance. Conversely, PTP1B-deficient mice have increased insulin sensitivity in muscle and liver. PTP1B also regulates leptin action; PTP1B-deficient mice have reduced adiposity due to increased leptin sensitivity in hypothalamus. Because transgenic PTP1B overexpression can cause insulin-resistance, at least in muscle, it is important to understand whether PTP1B overexpression in other insulin- and leptin target tissues contributes to insulin. My goal for this award is to obtain the necessary training in neuroscience and neuroendocrinology to determine the mechanism by which PTP1B regulates adiposity and energy balance. To determine whether PTP1B action on insulin and/or leptin signaling in hypothalamus regulates adiposity in vivo, we will generate transgenic mice overexpressing PTP1B selectively in POMC and AGRP/NPY neurons in the arcuate nucleus of hypothalamus. The effects on adiposiy and insulin sensitivity will provide important insights into the biological role of PTP1B in regulating whole body insulin sensitivity and adiposity. Pursuing these studies at BIDMC with Dr. Kahn, an expert in characterizing animal models of obesity and diabetes, and Dr. Elmquist, an expert in mapping leptin-responsive pathways in the CNS, will provide an exemplary environment for my research.